This invention relates to a method of enhancing the immunogenicity of T cell immunogenic peptides.
Only recently has the basis of recognition of protein antigens by helper T cells (Th) been defined in molecular terms. Th cells (i.e., CD4 positive) recognize a fragment or processed form of a foreign antigen bound to a class II major histocompatibility molecule (i.e., Ia) on the surface of an antigen presenting cell. See Unanue and Allen, Science 236, 551-557(1987), for a recent review.
Many different determinants of peptide antigens have been identified and characterized but the precise conformation of any of these peptides as they are bound to Ia and recognized by the T cell receptor is not known; proposed conformations have been made ranging from an alpha-helix to a beta-pleated sheet. For several years a group led by the present inventors has studied the immunogenic properties of a determinant of hen egg-white lysozyme (HEL) contained in the tryptic fragment encompassing residues 46-61. See Allen and Unanue, J. Immunol. 132, 1077 (1984); Allen et al., Proc. Natl. Acad. Sci. USA 81, 2489 (1984); Babbitt et al., Nature 317, 359 (1985); and Babbitt et al., Proc. Natl. Acad. Sci. USA 83, 4509-4513 (1986). The analysis revealed that the 10 amino acid peptide, HEL(52-61), was the smallest stimulatory peptide. Through the use of a series of substituted peptides, potential roles were assigned to each of the 10 amino acid residues in HEL(52-61) by Allen et al., Nature 327, 713-715 (1987). It was proposed that residues 53, 56, and 57 contacted the T cell receptor, residues 52, 58, and 61 contacted the Ia molecule, while residues 54, 55, 59, and 60 were spacer residues. When this peptide was modeled into an alpha-helix, a spatial segregation of the T cell contact residues from the Ia contact residues was observed. From this result it was proposed that HEL(52-61) was assuming an alpha-helical conformation as it bound to I-A.sup.k and as such was recognized by the appropriate T cell receptor.